We have recently shown that the killer cell immunoglobulin-like receptors (KIR) in combination with cognate MHC class I ligands determine the outcome of HCV infection. The goal of this project is to understand the mechanisms by which these interactions are protective. Specific Aim 1 studies KIR and MHC class I genetics to determine if this protection is present in the context of known doses and genotypes of HCV infection. Analysis of the presence or absence of specific KIR and MHC genes will be performed in individuals having received known inocula of HCV. Correlations of receptor-ligand combinations with the outcome of HCV infection will be sought. Specific Aim 2 tests the hypothesis that successful resolution of HCV infection is dependent on the strength of the KIR:MHC class I binding interaction. We will use cellular binding and flow cytometry assays to compare KIR binding to MHC class l-positive targets derived from individuals either clearing HCV infection or remaining persistently infected. Specific Aim 3 is a longitudinal analysis of NK cells in acute HCV infection in individuals undergoing self-limiting HCV infection, chronic HCV infection, a successful memory response and an unsuccessful memory response. The presence of NK cells with protective phenotypes will be sought by flow cytometry and real-time PCR analysis. These analyses will be combined with T cell analyses performed by Dr C Walker and Dr S Kalams to give an integrated picture of a successful and unsuccessful immune response to HCV. Hepatitis C virus affects 170 million individuals worldwide. Understanding how natural killer cells and their receptors assist in resolving acute HCV infection could lead to the generation of novel NK cell based therapies for individuals chronically infected with hepatitis C virus.